Androgenic compositions



Patented Sept. 4, 1951 ANDROGENIC ooMPosrrIoNs Arnold (J, Ott,Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo, Mich., acorpora o f Michigan No Drawing, Application Junefi, 19%9, Serial No.97485 Claims. (Cl. 167-7174) 1 T i i en o e ates t thera e icall us tulcompositions having an exceptionally pro? longed androgenic effect. Moreparticularly, this invention relates to testosteronebeta-cyclopentylpropionate and to androgenically active corn- 2 theaverage weight of the seminal vesicles determined and recorded. Thefollowing results were obtained:

Weight of Seminal vesicle in I) positions containing the said ester. lgr m e The esterification of the l7-hydroxyl group of 1209 1 9 4testosterone to produce certain esters having a 3 6 l 1 2 greater and amore prolonged effect than testodays days days days (lays days dayssterone is hown in United States Patent 2,109,400, lo T t t e em andtheir injectilm in l Solutions i wn b 97 270 522 525 e94 343 Miescher,Wettstein and lischopp, Biochem. J. 30, l 24 3. 13 0 37 1983 (1936,), Inthese references, it is clearly 1mg given) :8 9 t 1;; 9 0 s shown thatthe maximum efiectiveness of the E t re q l d i5 fil d n ab 12 110 16Testosterone beta-cyc1opentylpropionate can da s after injec ion. beprepared by reacting testosterone with beta- .I ha 9 e n. fo n t t h 111 wmcyclopentylpropionyl chloride (obtained from the p u s te o e eta cclop nt lpmpion action of thionyl chloride on beta-cyclopentyle h n in ein an 01 Solution, B9B on y gives a propionic acid), in the presence ofa tertiary base ma imu in the i h of t emi l such as pyridine ordimethylaniline, and there- Vesicle of a castrated Tat, much higher hant t after recovering the ester from the reaction mixobtai with p vi s yn n este te t tule. The acid bromide, obtained by the action temn b t heffect p sis s o a io up o of thionyl bromide (onbeta-cyclopentylpropionic days or lo low n a s g e i j ti nacid, may beused instead oi the acid chloride, if These facts are more clearly showndsirgg :5gta, gyplgpgntylpiropionate 3,159 be d II.- prepared by othermethods known to the art such Table I as hee int chan e f a lo e -a kvlte o Castrated rates, received on the firstexperibetaeyclopemylprppiomc. aciqwith testgstemng 1" by the az o r mc.ester catlon of te t stero e mental darn, e1 1 quantity of thedesignated ester with betwcyclopntylpropiomc acig inthe pres? equivalen0 ve milhgrams of testosterone, d1sgnce of benzene or toluene andpaIWtO-luene sub solved in peanut 011. At the end of each period foni Ic ar bo on t l uo e o ot er se ate of time indicated, five of theanimals were sacrilysts and'reactioh media i dicates thresult obtained,ventlon can be prepared by dissolving the ester in ether, mixing theother solution with a nontoxic, glyceride 'oil suitable for parentaladminisweightofseminalvesjclein tratiqn such as peanut, cottonseed, cornor semilligramsafter" same oil and removing the other under reducedOmpmmd 40 piessui c. The concentration of the ester in the 3 12 18 24oil is limited only by its solubility and stable soludays days days daysdays days days tions containing about 500 milligrams of testosteronebeta-cyolopentylpropionate per millimegg gg 52 5g; 4g ter have beenprepared. The use of ether or other es similar low boiling non-reactivesolvents speeds fl g gig cfi; 7 7 s 9 11 s 10 the solution of the esterin the oil, but their use is not essential, as the ester may bedissolved di- 1 rectly in the oil with stirring and gentle warm- Tabdg Hing, if desired.

Castrated rats received on the first experiment- For some purposes, itis desirable to add alumial day a quantity of the designated esterequivnum monostearate to the oil solution to obtain a alent to fivemilligrams of testosterone, dissolved thixotropic gel. Thixotropic gelsmay be prein peanut oil containing two percent aluminum pared by addingabout two percent by weight per monostearate. At the end of each periodof time volume of oil of aluminum monostearate to an indicated, six ofthe animals were sacrified and oil solution of the ester at roomtemperature.

- 3 The solution is then heated to about 120 degrees centigrade, held atthat temperature for about ten minutes and the solution thereaftercooled. A thixotropic gel results which is solid at ordinarytemperatures, but which will liquefy, if shaken.

The following examples are given to illustrate a method for preparingthe products of this invention, but the said invention is not to belimited thereto.

Example 1.-Testosterone beta-cyclopentylpropionate One and eight-tenthgrams of beta-cyclopentylpropionyl chloride [J. Chem. Soc. (1939), page1065] was added to a solution of 3.0 grams of testosterone in 7.0 gramsof dry pyridine at a substantially uniform rate over a period of tenminutes. The reaction temperature was maintained at about five degreescentigrade during the addition. The temperature of the mixture was thenraised to 26 degrees centigrade, and after being held there for four andone-half hours, the mixture was poured into 50 milliliters of coldaqueous G-normal sulfuric acid and extracted four times with25-milliliter portions of isopropyl ether. The ether extracts werecombined, washed with dilute acid, water,dilute sodium bicarbonate andwater. After drying, filtering and evaporating, light yellow crystalsformed which were recrystallized from normal hexane. There was thusobtained 3.4 grams (80 percent of the theoretical yield) of testosteronebeta-cyclopentylpropionate, melting at 101-102 degrees centigrade, [a]D+76.4 (chloroform).

Analysis:

Calculated for Carl-R103" C, 78.59 H, 9.77 Found 78.57 9.54

Example 2 A solution of three grams of dry, crystalline testosteronebeta-cyclopentylpropionate in 20 milliliters of ethyl ether was added,with stirring, to 100 milliliters of U. S. P. XII cottonseed oilcontained in a 300-milliliter balloon flask; The flask was fitted with acapillary ebullator attached to a stream of nitrogen, evacuated andwarmed on a steam bath. After about an hour, all of the other had beenremoved and a clear oil solution remained containing 30 milligrams permilliliter of testosterone beta-cyclopentylpropionate.

For the purpose of preservation, five milligrams of chlorobutanol permilliliter of solution may be added either to the hot oil or to theether solution of the ester.

In a similar manner, solutions of testosteronebeta-cyclopentylpropionate were prepared using sesame, peanut or cornoil.

Example 3 To vigorously stirred solution of three grams of testosteronebeta-cyclopentylpropionate in milliliters of peanut oil at 24 degreescentigrade, 1.9 grams of dry aluminum monostearate was added at asubstantially uniform rate over a period of five minutes. Thetemperature of the mixture was then raised at a rate of 10 degreescentigrade per minute until a temperature of 120 degrees centigrade wasobtained, and held at 120 degrees centigrade for 10 minutes. Stirringwas discontinued and the clear syrupy product was allowed to cool atroom temperature. There was thus obtained milliliters of a thixotropiegel containing 30 milligrams of testosterone betacyclopentylpropionateper milligram. Upon agitation, a free-flowing liquid was obtained whichis suitable for injection.

Various modifications may be made in the present invention withoutdeparting from the spirit or scope thereof, and it is to be understoodthat I limit myself only as defined in the appended claims.

I claim:

l. A therapeutic composition for parental administration having aprolonged androgenic efiect, comprising: a sterile solution oftestosterone beta-cyolopentylpropionat in a non-toxic vegetable oil.

2. A therapeutic composition for parental administration having aprolonged androgenic efiect, comprising: a sterile solution oftestosterone beta-cyclopentylpropionate and aluminum monostearate in anon-toxic vegetable oil.

3. A therapeutic composition for parental administration having aprolonged androgenic effect, comprising: a sterile solution oftestosterone beta-cyclopentylpropionate in peanut oil.

4. A therapeutic composition for parental ad ministration having aprolonged androgenic effeet after a single injection comprising asterile solution of testosterone beta-cyclopentylpropionate and abouttwo percent by weight of aluminum monostearate of the volume of the oilused in peanut oil.

5. Testosterone beta-cyclopenty1propionate.

ARNOLD C. OTT.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Name Date Miescher Feb. 22, 1938 OTHER REFERENCESNumber

5. TESTOSTERONE BETA-CYCLOPENTYLPROPIONATE.